Professor
Director of the Center for Breast Cancer Research
Associate Director of Education & Training, UNMC-Eppley Cancer Center
Co-Program Leader MBEP
Research Interests
Molecular Control of Receptor Tyrosine Kinase Signaling: Cell Biology and translational Implications
Summary of Research:
Dr. Band’s research laboratory is located on the 9th floor of Eppley Science Hall at UNMC-Eppley Cancer Center. The major focus of the laboratory is to define the elements of cancer cell signaling and use these to develop targeted therapeutics and early diagnostic/prognostic markers in cancer.
A major direction in the laboratory is to define the role of Cbl-family proteins, initially identified as proto-oncogene products, as negative regulators of signals initiated by tyrosine kinase-coupled cell surface receptors. This work follows directly from our discovery of Cbl as a major and ubiquitous substrate of a number of protein tyrosine kinases, and the demonstration of its physical associations with a number of crucial intracellular signal transduction proteins. Cbl has also emerged as a critical negative regulator of EGF and PDGF receptor tyrosine kinases, and Cbl-deficient mice exhibit a pronounced increase in mammary gland branching and hyper-cellularity of other organs. The targets of Cbl-mediated regulation in lymphocytes include Syk/ZAP70 tyrosine kinases as well as members of the Src-family kinases. Indeed, Cbl-deficient mice exhibit increased positive selection of CD4 cells, and Cbl-b-deficient mice are prone to spontaneous and/or induced autoimmunity and their T cells become co-stimulation-independent. Elucidation of the biochemical machinery that mediates the roles of Cbl as a negative regulator of receptor tyrosine kinases is therefore of great interest.
With three known mammalian Cbl family proteins, and the identification of C. elegans and Drosophila Cbl homologues, Cbl has gained substantial importance in cell biology as the core member of an evolutionarily conserved family of proteins involved in tyrosine kinase regulation. Our recent work has demonstrated that the evolutionarily conserved N-terminal transforming region of Cbl provides a tyrosine kinase-binding (TKB) domain that allows selective recruitment of Cbl to activated tyrosine kinases. Recently, we have shown that the RING finger domain of Cbl, which is also conserved through evolution, is essential for tyrosine kinase regulation. Together, the TKB and RING finger domains define a core region of Cbl family proteins that recruits the ubiquitin machinery for ubiquitination of activated tyrosine kinases. Recent work in our laboratory as well as the work of other groups now provides strong evidence for Cbl-mediated ubiquitination as a mechanism to control the level of tyrosine kinase signaling either by facilitating proteasome-mediated catabolism or targeting activated receptors to lysosomal degradation.
Our current work addresses the nature of the biochemical and cell biological machinery involved in tyrosine kinase regulation by Cbl. A major effort is underway to identify and characterize the endocytic machinery that recognizes the ubiquitin modification of Cbl-regulated receptors and helps sort these receptors into lysosomes. The focus of these studies is the mammalian ESCRT-1 (Endosomal Sorting Complex Required for Transport) complex, composed of the homologues of the yeast vacuolar protein sorting components VPS23, VPS28 and VPS37, together with its regulator VPS4. These new findings have led to a new direction in the laboratory to investigate the role of ubiquitin-dependent traffic of ErbB and PDGF receptors. Given the importance of controlling the intensity of a tyrosine kinase coupled receptors to ensure an appropriate level of cellular activity, and the dramatic consequences of aberrant tyrosine kinase activity, our basic studies carry far-reaching implications for understanding and possibly manipulating a number of pathological entities. For example, ErbB2, a major participant in the pathogenesis of breast and other epithelial cancers, is relatively resistant to Cbl-mediated negative regulation. Therefore, we have investigated if other ubiquitin ligases could downregulate ErbB2. These studies have led to the identification of a molecular chaperone-associated ubiquitin ligase CHIP as a mediator of ErbB2 downregulation upon HSP90 inhibition. As HSP90 inhibitors are now in clinical development as anticancer agents, these studies provide a strong translational potential for breast cancer therapy. In particular, our laboratory is investigating the possibility of combining CHIP and Cbl ubiquitin ligase pathways for potentiation of anti-ErbB2 therapy.
Activated receptor tyrosine kinases that are not sorted to lysosomes continue to signal intracellularly and are eventually recycled to the cell surface for repeated cycles of signaling. This is a pattern seen with ErbB2 and accounts for its signaling superiority and higher oncogenic potential. Therefore, we are investigating the nature of intracellular signals that emanate from internalized ErbB receptors and the nature of molecular machinery that controls the duration of their intracellular transit and final recycling. These studies focus on the role of Src-family tyrosine kinases, which are known to collaborate with ErbB receptors and on a new family of recycling endocytic proteins with EH domains – the EHD protein family. As a new addition to these studies, we are also investigating the cell biology of mutant EGF receptors involved in human cancers, such as those isolated from human non-small cell lung cancer patients. Our basic cell biological and biochemical studies are aimed at understanding a fundamental cellular process and at translating these lessons into clinical practice to develop targeted therapies against cancer and/or to improve current therapeutic regimens.
Dr. Band’s research is supported by the National Cancer Institute of the National Institutes of Health. Past work has been supported by the NCI/NIH, Department of Defense Breast Cancer Research Program, Avon Foundation, the NCI SPORE in Breast Cancer at Northwestern University and the NCI Center for Cancer Nanotechnology Excellence at Northwestern University.
Link to Publications on Pubmed
Tel: (402) 559-8572 (Office)
E-mail: Hamid Band